EP2498833B1 - Utilisation d'agents polymériques ou oligomériques pour des articles médicaux - Google Patents

Utilisation d'agents polymériques ou oligomériques pour des articles médicaux Download PDF

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Publication number
EP2498833B1
EP2498833B1 EP10778649.3A EP10778649A EP2498833B1 EP 2498833 B1 EP2498833 B1 EP 2498833B1 EP 10778649 A EP10778649 A EP 10778649A EP 2498833 B1 EP2498833 B1 EP 2498833B1
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EP
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Prior art keywords
diamine
polymeric
triamine
oligomeric active
component
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EP10778649.3A
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German (de)
English (en)
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EP2498833A1 (fr
Inventor
André Weiss
Thomas Riemann
Martin Sippel
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B Braun Melsungen AG
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B Braun Melsungen AG
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/14—Materials characterised by their function or physical properties, e.g. lubricating compositions
    • A61L29/16—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/04—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/04—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N47/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid
    • A01N47/40—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having a double or triple bond to nitrogen, e.g. cyanates, cyanamides
    • A01N47/42—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having a double or triple bond to nitrogen, e.g. cyanates, cyanamides containing —N=CX2 groups, e.g. isothiourea
    • A01N47/44—Guanidine; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/204—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials with nitrogen-containing functional groups, e.g. aminoxides, nitriles, guanidines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/404—Biocides, antimicrobial agents, antiseptic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C277/00—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T428/00—Stock material or miscellaneous articles
    • Y10T428/13—Hollow or container type article [e.g., tube, vase, etc.]
    • Y10T428/1352—Polymer or resin containing [i.e., natural or synthetic]
    • Y10T428/139—Open-ended, self-supporting conduit, cylinder, or tube-type article

Definitions

  • the invention relates to the use of polymeric or oligomeric active substances having a biocidal effect as an additive in a composition for medical articles.
  • the invention relates to a method for producing a medical article and a medical article.
  • Medical articles introduced into the body of a patient such as intravascular catheters, breathing tubes or stents, must have as smooth a surface as possible to minimize discomfort to the patient as well as deposits on the surface.
  • These medical articles and their packaging are often made by the process of plastics technology, such as molding, injection molding, thermoforming and extrusion of a plastic, trying to achieve the smoothest possible surfaces.
  • the medical articles be equipped with antimicrobial agents.
  • High demands are placed on the biocidal equipment of the medical articles, since the articles come into contact with body tissue and body fluid.
  • catheters inserted through the skin surface into arteries or veins, but also wound or thoracic drainage tubes, are frequent sources of infection.
  • patients who require long-term urinary catheters are at risk of developing urinary tract infections that may be bacterial or chronic Can cause pyelonephritis.
  • central venous catheters play an increasingly important role in medical treatments and surgical procedures.
  • Central venous catheters are being used more and more often in the context of intensive care medicine, but also in applications such as bone marrow and organ transplantation, hemodialysis or cardiothorax surgery.
  • the medical articles especially the catheters, but not only the high demands on a smooth surface, for example to prevent or reduce platelet apposition and biofilm formation and the biocidal equipment that prevent microbial growth on the surface or kill the microbes completely should be ensured, but it must also be ensured that the biocidal equipment of medical items does not adversely affect the material properties of medical articles.
  • the medical articles in particular, when they come into contact with liquid, on the one hand have a high biocidal efficacy, but on the other hand are not released to the liquid in order to avoid an accumulation of biocidal agents in the body.
  • the delivery of a biocidal drug from a medical article upon fluid contact is also referred to as "leaching.”
  • From the EP 0 229 862 are known polyurethane medical articles on the surface of which an antimicrobial agent is applied.
  • From the EP 0 379 269 are also medical articles, in particular hoses, which are molded from a thermoplastic polymer and containing as an antimicrobial agent chlorhexidine. These articles are made by first providing a blend of chlorhexidine and plastic granules of a thermoplastic polymer which is made into a melt in which the chlorhexidine is evenly distributed, the melt being extruded through a matrix to form the medical article.
  • biocidal agents based on biguanides such as chlorhexidine or polyhexamethylene biguanide, is not always satisfactory.
  • WO 2009/009814 A2 discloses a polymeric dental material comprising a siliceous filler modified with a polymeric guanidine derivative based on an alkylenediamine and / or an oxyalkylenediamine.
  • a polymeric guanidine derivative poly [2- (2-ethoxyethoxyethyl) guanidium hydrochloride] which, however, has not given satisfactory antimicrobial efficacy and biocompatibility benefits for applications of class 3 medical devices in direct contact with the bloodstream provided.
  • biocidal active substances which are intended for the production of medical articles.
  • the biocidal active ingredients must adequately soften under the conditions of the processing technology, namely the thermoplastic shaping, such as extrusion or injection molding and the temperatures and pressures occurring, must not decompose and must also be compatible with the other plastic components of the medical article.
  • the object of the present invention is achieved by the use of novel polymeric or oligomeric active substances as additives to materials for medical articles.
  • the polymeric or oligomeric active substances to be used according to the invention have good biocompatibility, have high antimicrobial activity against a large number of germs and, moreover, only a slight influence on the thermoplastic polymers required for the manufacture of the medical articles. in terms of strength, gloss and durability.
  • the polymeric or oligomeric active compounds used according to the invention can be present both as a homopolymer and as a copolymer. It is advantageous if the guanidine acid addition salt is guanidinium hydrochloride. However, other guanidine acid addition salts based on inorganic or organic acids are also suitable. For example, the hydroxides, hydrogen sulfates and acetates.
  • the polymeric or oligomeric active compounds used according to the invention are preferably in the form of a hydroxide salt. These may be prepared, for example, by basic anion exchange from the corresponding halides, e.g. Chlorides are obtained.
  • the polymeric or oligomeric active compounds obtainable by the polycondensation in this case preferably have a polyguanidine structure or, in particular in the case of the use of dialkylenetriamines, for example diethylenetriamine, a poly (iminoimidazole) structure.
  • the amine mixture comprises component i) (diamine which has at least one cycloaliphatic radical) and / or component ii) (dialkylenetriamine) in an amount of at least 10 mol%, preferably at least 25 mol% , more preferably at least 45 mol%, in particular at least 85 mol%, in particular at least 95 mol%, in each case based on the total amine mixture.
  • Suitable oxyalkylene diamines are in particular those oxyalkylene diamines which have terminal amino groups.
  • a preferred oxyalkylenediamine is a compound of the general formula NH 2 [(CH 2 ) 2 O)] n (CH 2 ) 2 NH 2 in which n is an integer between 2 and 6, preferably between 2 and 5, more preferably between 2 and 4 and in particular 2.
  • Polyoxypropylene diamines, in particular di- or tripropylene glycol diamine can furthermore preferably be used.
  • the polymeric or oligomeric drug is present as a homopolymer.
  • the amine mixture consists of a diamine having at least one cycloaliphatic radical or of a dialkylene triamine.
  • the amine mixture consists of the triamine diethylenetriamine.
  • the polymeric or oligomeric active ingredient is thus present as homopolymer, for example as poly (iminoimidazole).
  • the amine mixture consists of the diamine 4,4'-methylenebis (cyclohexylamine).
  • a guanidine acid addition salt for example, the homopolymer poly (4,4'-methylenebis (cyclohexylamine hydrochloride)) is formed therefrom.
  • the polymeric or oligomeric active compounds obtainable by polycondensation of a guanidine acid addition salt with an amine mixture which comprises at least one diamine having at least one cycloaliphatic radical.
  • Diamines which have at least one cycloaliphatic radical are, for example, cycloaliphatic diamines, for example cyclohexanediamine, cyclopentanediamine and derivatives thereof.
  • Particularly preferred are those diamines in which at least one NH 2 group is linked directly to the cycloaliphatic radical.
  • Particularly preferred are those diamines in which both NH 2 groups are each directly linked to one and the same cycloaliphatic radical or to various cycloaliphatic radicals.
  • the amine mixture comprises 4,4'-methylenebis (cyclohexylamine).
  • the amine mixture comprises at least one dialkylenetriamine.
  • the dialkylenetriamines can have alkylene radicals of different chain lengths. However, preference is given to dialkylenetriamines in which the alkylene groups have the same length.
  • Preferred alkylene radicals are ethylene, propylene and butylene and hexylene.
  • the amine mixture comprises the triamine diethylenetriamine.
  • Particularly suitable copolymers or cooligomere active ingredients have been found to be those in which the first component is 4,4'-methylenebis (cyclohexylamine) and the second component is selected from diethylenetriamine, hexamethylenediamine and triethyleneglycol diamine.
  • the copoylmere guanidine derivative as the first component contains diethylenetriamine and the second component is selected from the group consisting of hexamethylenediamine and triethyleneglycol diamine.
  • copolymeric guanidine derivatives have been found to be particularly suitable in which at least one component Alkylenediamine, especially hexamethylenediamine, is.
  • polymeric or oligomeric active compounds obtainable by polycondensation of a guanidic acid addition salt with an amine mixture in which the first component is diethylenetriamine and / or 4,4'-methylenebis (cyclohexylamine) and the second component is hexamethylenediamine.
  • amine mixtures comprising diethylenetriamine and hexamethylenediamine.
  • the available active ingredients do not show only excellent antibacterial properties, but are also biocompatible, what these drugs especially for medical articles that are in direct contact with the bloodstream, is suitable.
  • the first component may be diamine having at least one cycloaliphatic radical, and / or a dialkylenetriamine, and the second component an oxyalkylene diamine, especially triethylene glycol diamine.
  • the mixing ratio of the amines to be used can be varied within wide limits. However, preference is given to copolymers or cooligomeric active ingredients in which the monomers of the amine mixture, ie the first component and the second component, are present in a molar ratio of 4: 1 to 1: 4, preferably 2: 1 to 1: 2.
  • the polymeric or oligomeric active substances to be used according to the invention preferably have an average molecular weight (weight average) in the range from 500 to 7000, in particular from 1000 to 5000 daltons.
  • the polymeric or oligomeric active ingredients used according to the invention all have an antibacterial effect which can be described by means of the so-called "minimal inhibitory concentration". This indicates the lowest bactericidal concentration that inhibits the growth of bacteria in a given solution. Particularly favorable is a minimum inhibitory concentration of less than 50 ug / ml.
  • the polymeric polymeric or oligomeric active ingredients to be used according to the invention preferably have a minimum inhibitory concentration of less than 10 ⁇ g / ml, in particular less than 5 ⁇ g / ml. The lower this concentration, the more effectively the corresponding polymeric or oliogmere agent can be used as a biocide.
  • the polymeric or oligomeric active substances to be used according to the invention have a minimum inhibitory concentration of 50 ⁇ g / ml or less, preferably 30 ⁇ g / ml or less, more preferably 10 ⁇ g / ml or less and in particular 5 ⁇ g / ml or less.
  • the polymeric or oligomeric active substances to be used according to the invention can be prepared relatively easily.
  • the polycondensation can be carried out by mixing one equivalent of an acid addition salt with one equivalent of the amine mixture and then heating, preferably in a range of 140 to 180 ° C and stirring the melt at elevated temperatures, preferably in a range of 140 to 180 ° C until gas evolution finished, done.
  • the polycondensation is carried out regularly in a period of several hours, in which the melt is preferably stirred in the temperature range of 140 to 180 ° C.
  • a preferred reaction period is 1 to 15 hours, preferably 5 to 10 hours.
  • the process varies slightly, so it is favorable for the preparation of the homopolymer based on 4,4'-methylenebis (cyclohexylamine), when the reaction temperature is 170 ° C.
  • the homopolymer prepared on the basis of diethylenetriamine can be recovered at 150 ° C.
  • the preparation of the copolymeric active ingredients to be used according to the invention is again preferably carried out in a temperature range of about 170.degree.
  • cyclic structures for example iminoimidazole structures
  • the active compounds to be used according to the invention are not only polymeric or oligomeric guanidine derivatives, but also polymers or polymers can act oligomeric Iminoimidazolderivate.
  • the polymeric or oligomeric active ingredients are used as additives in compositions for medical articles.
  • the compositions for the medical article in a preferred embodiment, in an amount of not more than 10.0 wt .-%, preferably in one Amount of 0.01 to 5 wt .-% and in particular in an amount of 1.0 to 4.0 wt .-%, each based on the composition for the medical article containing.
  • a particular advantage of the polymeric or oligomeric active substances to be used according to the invention is their incorporation into plastics, in particular thermoplastic polymers, which frequently form the essential constituent of compositions for medical articles. It has surprisingly been found that the polymeric or oligomeric active ingredients can not only be incorporated without problems into plastics, in particular thermoplastic polymer compositions, but moreover that the mechanical properties, such as, for example, the tensile strength or the bending resistance, are only insignificantly influenced. In addition, it has surprisingly been found that the use of the polymeric or oligomeric active ingredients in compositions comprising plastics, in particular thermoplastic polymers, for medical articles during processing leads to extremely smooth surfaces and moreover has a controllable "leaching" effect.
  • the biocidal polymeric or oligomeric active ingredients can be processed so that they are not released from liquids such as water or ethanol from the polymer blend, which is important for medical articles such as catheters, for example.
  • targeted release may also be desirable, for example in wound dressings.
  • the compositions provided with the polymeric or oligomeric active ingredients in particular compositions comprising thermoplastic polymers for medical articles, have excellent properties antimicrobial efficacy, although they have no leaching effect as in the case of catheter applications.
  • the composition for medical articles further comprises plastics, preferably thermoplastic polymers, in particular selected from polyurethane, polyolefin, polyvinyl chloride, polycarbonate, polystyrene, polyethersulfone, silicone and polyamide.
  • plastics preferably thermoplastic polymers, in particular selected from polyurethane, polyolefin, polyvinyl chloride, polycarbonate, polystyrene, polyethersulfone, silicone and polyamide.
  • the medical article compositions comprise polyurethane, polyethylene or polypropylene.
  • the oligomeric or polymeric active ingredient may also be covalently bonded to the thermoplastic polymer.
  • the compositions for the medical articles at least 50 wt .-%, preferably at least 75 wt .-% and in particular at least 95 wt .-% of the oligomeric or polymeric active ingredients used, covalently bonded to the thermoplastic, before.
  • the medical article compositions may contain other common additives.
  • inert fillers in question.
  • Particularly suitable is barium sulfate.
  • a suitable BaSO 4 can be purchased under the trade name Blancfix ® from Sachtleben Chemie GmbH.
  • the fillers are preferably present in the compositions for medical articles in an amount of from 10 to 35% by weight, based on the total mixture.
  • the fillers have an average particle size of 0.01 .mu.m to 10 .mu.m.
  • the composition is substantially free of siliceous fillers, as these may adversely affect the surface smoothness as well as the leaching effect.
  • siliceous fillers in an amount below 1 wt .-%, preferably below 0.5 wt .-%, more preferably below 0.01 wt .-% and in particular free of any siliceous fillers, wherein the weight data refer to the total weight of the composition for the manufacture of the medical article.
  • Medical articles within the meaning of the present invention are in particular selected from the group consisting of central nervous catheters; peripheral venous catheters; Breathing tubes; stent; Products for use in regional anesthesia, in particular catheters, hairpins, filters; Infusion therapy products, in particular containers, ports, transfer systems, filters; Accessories such as connectors, spikes, valves, three-way valves, syringes, lines, injection ports; Products of preparation, in particular transfer sets, mix sets; urological products, in particular catheters, urine measuring and collecting apparatus; Wound drainage; Wound care; surgical sutures; Implantation aids and implants, in particular plastic implants, for example hernia meshes, nonwovens, knitted fabrics, knitted fabrics, ports, port catheters, vascular prostheses; Disinfectants; disposable surgical instruments; Chest tubes; probes; Catheter; Housings of medical devices, in particular infusion pumps, dialysis machines and monitors; artificial dentures; Container for liquids, in particular contact lens container.
  • Medical articles in the context of the present invention also cover accessories for medical products, such as injection-molded parts and molded parts. Of particular importance is the use of polymeric or oligomeric agents as an additive in surgical suture coatings.
  • a preferred medical article in the context of the present invention is a wound dressing.
  • Particularly preferred medical articles are tubular medical articles. Such articles have at least one tubular component.
  • Tubular medical articles within the meaning of the present invention are those medical articles that can carry fluids.
  • the medical articles are selected from the group consisting of catheters; central venous catheters; peripheral venous catheters; Breathing tubes; stent; Knoll lungs; ports; From pipelines; Connectors, spikes, valves, three-way valves, syringes, lines, injection ports; Wound drainage; Chest drainage and probes.
  • Particularly preferred medical articles are catheters, especially those made by extrusion of compositions comprising polyurethane and / or polyethylene and / or polyamide.
  • a particularly suitable polyamide under the trade name Pebax ® (Arkema) are available. It is a polyamide containing polyether blocks.
  • the polymeric or oligomeric active ingredients are also suitable as an additive for detergents or disinfectants, in particular hand disinfectants.
  • Preferred polymeric or oligomeric active ingredients and preferred plastics correspond to those mentioned above.
  • the mixing in step a) is preferably carried out by melt kneading.
  • the polymeric guanidine derivative can be added as an aqueous solution to the molten plastic and then mixed in an extruder.
  • the melt kneading is carried out at temperatures above 100 ° C, more preferably above 150 ° C.
  • the polymeric or oligomeric active ingredient is preferably fed to the shaping process in step b) as granules or masterbatch.
  • the production of granules can be carried out by methods familiar to the person skilled in the art in the field of plastics technology.
  • the masterbatch is preferably a granulate which has the polymeric or oligomeric active ingredient in a higher concentration than the intended final concentration in the medical article. When using a masterbatch this is therefore further diluted by the addition of further plastic to the desired final concentration.
  • the shaping method used in step b) of the method according to the invention is preferably an extrusion method.
  • tubular components of the catheter can be made herewith.
  • the shaping processes are preferably carried out at temperatures above the melting point of the mixture prepared in step a), particularly preferably in a temperature range above 160 ° C., more preferably in a range of 180-260 ° C.
  • the result is a material with antimicrobial properties in which the additive (polymeric or oligomeric active ingredient) physically mixed or possibly chemically bonded to the respective plastic.
  • thermoplastic polymer to be used in the medical article according to the invention and in the method according to the invention is preferably a thermoplastic polyurethane. It has been found to be particularly suitable polyurethanes consisting of a combination of 4,4'-diphenylmethane diisocyanate (MDI) and a polyol based on polyester or polyether.
  • the polyol comprises a polytetramethylene glycol ether.
  • suitable thermoplastic polymers which are preferably suitable for compositions of the medical articles according to the invention are, for example, selected from polyurethane, polyolefin, polyvinyl chloride, polycarbonate, polystyrene, polyethersulfone, silicone and polyamide.
  • the medical article compositions comprise polyurethane, polyethylene or polypropylene or polyamide.
  • Preferred medical articles are the same as those mentioned above. Particularly preferred medical articles are wound dressings and catheters.
  • the flask is equipped with an internal thermometer and a threefold heated reflux condenser with non-return valve according to Stutz (in the following section cooler).
  • reaction mixture In an oil bath, the reaction mixture is heated, starting from a temperature of 100 ° C, a slow evolution of gas begins. With further increase in temperature, the gas evolution is only slowly stronger. After a total of 85 minutes, a temperature of 170 ° C is reached.
  • the melt is cooled to room temperature.
  • the starting amounts used give under the conditions mentioned above 24.48 g of a transparent, colorless and brittle solid.
  • the structure of the obtained polymer can be represented by the formula (I).
  • N 1 to 8, predominantly 1 to 3.
  • the resulting product mixture thus contains polymeric compounds corresponding to the formulas (II), (III) and (IV): where n is defined as in formula (I).
  • the melt is kept under stirring for five hours at 150 ° C until gas evolution is complete.
  • the melt Under ice-cooling and oil vacuum, the melt is cooled to room temperature.
  • the starting amounts used give under the conditions mentioned above 11.96 g of a white and brittle solid.
  • n 1 to 12, predominantly 2 to 8.
  • R3 is either NH 2 or and R4 is selected from
  • the resulting product mixture thus contains polymeric compounds corresponding to the formulas (VI), (VII) and (VIII):
  • Example 2 can be represented in an analogous manner, wherein the positive charge mesomerically distributed to all three nitrogen atoms of the guanidine unit.
  • Monomer 1 Monomer 2 Amount used monomer 1 Amount used monomer 2 C1 4,4'-methylenebis (cyclohexyl-amin) diethylenetriamine 14.30 g 2.21 g 68 mmol 17 mmol 0.80 eq 0.2 eq C2 4,4'-methylenebis (cyclohexyl-amin) diethylenetriamine 13.41 g 2.77 g 63.75 mmol 21.25 mmol 0.75 eq 0.25 eq C3 4,4'-methylenebis (cyclohexyl-amin) diethylenetriamine 11.92 g 3.69 g 56.67 mmol 28.33 mmol 0.67 eq 0.33 eq C4 4,4'-methylenebis (cyclohexyl-amin) diethylenetriamine 8.94 g 5.53 g 42.50 mmol 42.50 mmol 0.50 eq 0.50 eq C5 4,4'-methylenebis (cyclohexyl-amin) Hex
  • the compounds prepared according to one of the preceding examples are prepared in a bacterial nutrient medium, preferably Tryptic Soy Broth, and diluted to various concentrations.
  • the minimum inhibitory concentration (MIC) is then understood as meaning the lowest concentration of the biocide to be investigated in the solution in which the growth of the bacteria is inhibited. In the case of the corresponding solution, no cloudiness due to the growth of the bacteria is then observable.
  • Formula (V) > 250 C13 8.5 C1 7.5 C14 10 C2 22.5 C15 10 C3 25 C16 10 C4 50 C17 3 C5 1.5 C18 10 C6 4.7 C19 10 C7 4.25 C20 40 C8 2.5 C21 > 50 C9 3.5 C22 > 50 C10 2.5 C23 > 50
  • the control used was a control polymer whose biocidal activity is known and whose minimum inhibitory concentration is usually 5 ⁇ g / ml.
  • the active ingredient is the product of a polycondensation of a guanidine acid addition salt with an amine mixture containing at least one diamine and / or one triamine, if at least one amine is selected from 4,4'-methylenebis (cyclohexylamine) and diethylenetriamine.
  • a guanidine acid addition salt guanidine hydrochloride.
  • the polymeric or oligomeric agent may be a homopolymer. It is advantageous if the amine mixture consists of the triamine diethylenetriamine or if the amine mixture consists of the diamine 4,4'-methylenebis (cyclohexylamine).
  • the amine mixture may contain a first component and at least one second component, wherein the first component is a diamine or a triamine selected from the group consisting of 4,4'-methylenebis (cyclohexylamine), diethylenetriamine, and wherein the second component is a diamine or a triamine selected from the group consisting of 4,4'-methylenebis (cyclohexylamine), diethylenetriamine, hexamethylenediamine, triethyleneglycol-diamine, and wherein the first component is different from the second component.
  • the first component is a diamine or a triamine selected from the group consisting of 4,4'-methylenebis (cyclohexylamine), diethylenetriamine, hexamethylenediamine, triethyleneglycol-diamine, and wherein the first component is different from the second component.
  • the first component is 4,4'-methylenebis (cyclohexylamine) and the second component is selected from diethylenetriamine, hexamethylenediamine, triethyleneglycol diamine. It is also favorable if the first Component is diethylenetriamine and the second component is selected from hexamethylenediamine and triethyleneglycol diamine.
  • the first component and the second component are preferably present in a mixing ratio of 4: 1 to 1: 4.
  • the amine mixture and the guanidine salt are preferably used in approximately equimolar to each other.
  • the active substance is the product of a polycondensation of a guanidine acid addition salt with an amine mixture containing at least one diamine and / or a triamine
  • Example 5 General procedure for producing a polyurethane-based catheter tube from TPU granules equipped with the polymeric or oligomeric active substance to be used according to the invention
  • thermoplastic polyurethane based on a polytetramethylene glycol ether
  • barium sulfate having an average particle size of 0.01 .mu.m to 10 .mu.m and 0.5 to 10 wt. % of a polymeric or oligomeric active substance to be used according to the invention is mixed and then extruded.
  • the extrusion takes place with extruders customary for catheter production, for example the maillefer type ED 45-30D extruder.
  • thermoplastic polyurethane Pellethane ® 2363-90 A (Lubrizol Advanced Materials, USA) with 25 wt .-% barium sulfate with a medium Grain size of 0.7 .mu.m and 3 wt .-% of the active ingredient C20 mixed and then extruded. Extrusion took place with the Maillefer ED 4530D extruder at temperatures above 160 ° C.
  • a catheter piece according to Example 6 is produced, but without the addition of a polyguanidine.
  • the catheter tube pieces produced according to Examples 6 and 7 were examined by scanning electron micrographs. It could already be determined optically that the catheter tube pieces according to the invention were designed significantly smoother than the catheter tube pieces according to Comparative Example 7.
  • the surface roughness R z [ ⁇ m] was measured.
  • a surface roughness R z of 2.91 ⁇ m and for the catheter tube piece according to the invention according to example 6, only a surface roughness R z of 2.32 ⁇ m was determined.
  • a catheter tube according to Example 6 is prepared, but instead of the polyguanidine to be used according to the invention, the poly [2- (2-ethoxyethoxyethyl) guanidinium hydrochloride] is used in an amount of 3% by weight.
  • Example 6 The catheter tube pieces according to Example 6 (according to the invention) and according to Comparative Example 8 were subjected to a proliferation test.
  • the proliferation test is based on the publication Nature Medicine, Vol. 6, no. 8, 1053-1056; 2000 ,
  • the catheter tube pieces to be examined are contaminated with different germs and then observed the germ growth in comparison to a sample that is not equipped antimicrobial.
  • the time needed for germination to reach a given value (0.2 onset OD) relative to a non-antimicrobial sample is measured. more the longer the time, the higher the antimicrobial effectiveness of the sample against the individual germs.
  • Table 4 shows the results of the proliferation test using different germs. ⁇ b> Table 4 ⁇ / b> germ
  • Example 8 [h]
  • Example 6 [h] MRSA 21.0 48.0 Staphylococcus epidermidis 35.5 48.0 Staphylococcus aureus 26.8 48.0 Pseudomonas aeruginosa 0.1 48.0 Enterococcus faecalis 0.3 48.0 Klebsiell pneumoniae 48.0

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Claims (15)

  1. Utilisation d'un principe actif polymère ou oligomère à effet biocide qui peut être obtenu par la polycondensation d'un sel d'addition acide de guanidine avec un mélange d'amines contenant au moins une diamine et/ou une triamine, au moins une amine étant choisie dans le groupe consistant en
    i) une diamine présentant au moins un reste cycloaliphatique, et
    ii) la dialkylène triamine,
    en tant qu'additif dans une composition destinée à des articles médicaux.
  2. Utilisation selon la revendication 1, caractérisée en ce que ledit mélange d'amines comprend la diamine 4,4'-méthylènebis(cyclohexylamine).
  3. Utilisation selon au moins une des revendications 1 ou 2, caractérisée en ce que ledit mélange d'amines contient un premier composant et au moins un second composant, dans laquelle
    a) ledit premier composant est une diamine ou triamine choisie dans le groupe consistant en
    i) une diamine présentant au moins un reste cycloaliphatique, et
    ii) une dialkylène triamine, et dans laquelle
    b) ledit second composant est une diamine ou triamine choisie dans le groupe consistant en
    i) une diamine présentant au moins un reste cycloaliphatique,
    ii) une dialkylène triamine,
    iii) une alkylène diamine et
    iv) une oxyalkylène diamine, et
    dans laquelle ledit premier composant est différent dudit second composant.
  4. Utilisation selon au moins une des revendications 1 à 3, caractérisée en ce que ledit principe actif polymère ou oligomère est un dérivé d'iminoimidazole.
  5. Utilisation selon au moins une des revendications 1 à 4, caractérisée en ce que ledit principe actif polymère ou oligomère présente une structure choisie dans le groupe comprenant
    Figure imgb0029
    Figure imgb0030
    Figure imgb0031
    Figure imgb0032
    Figure imgb0033
     où
    HCl* signifie que le HCl n'est pas lié de manière covalente,
    n est un entier naturel, de préférence de 1 à 20, plus préférablement de 2 à 16, notamment de 3 à 8,
    p, q et r sont des entiers définissant le rapport molaire mutuel préféré des fragments structuraux dans les formules.
  6. Utilisation selon au moins une des revendications 1 à 5, caractérisée en ce que ledit principe actif polymère ou oligomère présente un poids moléculaire moyen compris entre 500 et 7000, notamment entre 1000 et 5000.
  7. Utilisation selon au moins une des revendications 1 à 6, caractérisée en ce que ledit dérivé polymère de guanidine est présent en une quantité d'au plus 10,0 % en poids, notamment de 0,01 à 5 % en poids, et spécifiquement en une quantité de 1,0 à 4,0 % en poids, par rapport à ladite composition destinée audit article médical.
  8. Utilisation selon au moins une des revendications 1 à 7, caractérisée en ce que ladite composition comprend en outre au moins une matière plastique, de préférence au moins un polymère thermoplastique, notamment choisi parmi polyuréthane, polyoléfine, polychlorure de vinyle, polycarbonate, polystyrène, polyéthersulfone, silicone et polyamide.
  9. Utilisation selon au moins une des revendications 1 à 8, caractérisée en ce que ledit article médical est choisi dans le groupe consistant en des cathéters veineux central, des cathéters veineux périphérique, des tubes respiratoires, des endoprothèses, des produits destinés à être appliqués dans l'anesthésie régionale, notamment des cathéters, des couplages, des filtres ; des produits destinés à la thérapie par infusion, notamment des récipients, des prises, des systèmes de transition, des filtres ; des accessoires, comme des connecteurs, des aiguilles, des valves, des robinets à trois voies, des seringues, des conduits, des ouvertures à injection ; des produits de formulation, notamment des ensembles de transfert, des ensembles de mixage ; des produits urologiques, notamment des cathéters, des dispositifs de mesure et de collection d'urine ; des drains de plaie ; des pansements pour plaies ; des matériaux de suture chirurgicale ; des accessoires d'implantation et des implants, notamment des implants en matière plastique, par exemple, des bandages herniaires, des non-tissés, des tricots, des tissus de mailles, des prises, des cathéters à chambre implantables, des prothèses vasculaires ; des désinfectants ; des instruments chirurgicaux jetables ; des drains thoraciques ; des sondes ; des cathéters ; des boîtiers pour dispositifs médicaux, notamment pour les pompes à infusion, les dispositifs de dialyse et les écrans, des dentures artificielles ; des récipients pour liquides, notamment des étuis pour lentilles de contact ; des produits de nettoyage et des désinfectants.
  10. Procédé pour la production d'un article médical, comprenant les étapes consistant à :
    a) combiner et mélanger un principe actif polymère ou oligomère à effet biocide qui peut être obtenu par la polycondensation d'un sel d'addition acide de guanidine avec un mélange d'amines contenant au moins une diamine et/ou une triamine, au moins une amine étant choisie dans le groupe consistant en
    i) une diamine présentant au moins un reste cycloaliphatique, et
    ii) la dialkylène triamine,
    avec au moins une matière plastique, notamment un polymère thermoplastique ;
    b) soumettre le mélange obtenu dans l'étape a) dans un ou plusieurs procédés de façonnage pour former un article médical.
  11. Procédé selon la revendication 10, caractérisé en ce que ledit principe actif polymère ou oligomère est soumis audit procédé de façonnage dans l'étape b) sous forme de granules ou de mélange-maître.
  12. Procédé selon la revendication 10 ou 11, caractérisé en ce que le mélange dans l'étape a) est effectué dans une extrudeuse.
  13. Procédé selon au moins une des revendications 10 à 12, caractérisé en ce que ledit procédé de façonnage est une extrusion.
  14. Article médical, comprenant un principe actif polymère ou oligomère à effet biocide qui peut être obtenu par la polycondensation d'un sel d'addition acide de guanidine avec un mélange d'amines contenant au moins une diamine et/ou une triamine, au moins une amine étant choisie dans le groupe consistant en
    i) une diamine présentant au moins un reste cycloaliphatique, et
    ii) la dialkylène triamine,
    et au moins une matière plastique.
  15. Article médical selon la revendication 14, caractérisé en ce qu'il s'agit d'un article médical tubulaire, notamment d'un cathéter.
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CN106366620A (zh) * 2016-08-30 2017-02-01 何仁英 一种含有聚氨酯的输液袋材料及其制备方法
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BR112012011218A2 (pt) 2016-04-05
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WO2011058148A1 (fr) 2011-05-19
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US20120282213A1 (en) 2012-11-08
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ES2456698T3 (es) 2014-04-23
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